Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.
Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.
复制标题
在早衰症小鼠模型中，增强 ATM 活性可减轻衰老并延长寿命。
作者：
Qian M;Liu Z;Peng L;Tang X;Meng F;Ao Y;Zhou M;Wang M;Cao X;Qin B;Wang Z;Zhou Z;Wang G;Gao Z;Xu J;Liu B
DNA损伤随着年龄的增长而积累（Lombard等人，2005年）。然而，强大的DNA修复机制是否以及如何促进长寿是难以捉摸的。在这里，我们证明了以ATM为中心的DNA损伤反应（DDR）随着衰老和年龄的增长而逐渐下降，而低剂量的氯喹（CQ）激活ATM，促进DNA损伤清除，挽救与年龄相关的代谢转变，并延长复制寿命。在分子上，ATM使SIRT 6脱乙酰酶磷酸化，从而阻止MDM 2介导的泛素化和蛋白酶体降解。额外的Sirt 6拷贝延长了Atm-/-小鼠的寿命，恢复了代谢稳态。此外，用CQ处理显著延长秀丽隐杆线虫的寿命，而不是ATM-1突变体。在具有低DNA修复能力的早衰小鼠模型中，长期施用CQ改善了过早衰老特征并延长了寿命。因此，我们的数据突出了ATM的促长寿作用，首次在强大的DNA修复机制和长寿之间建立了直接的因果关系，并为早衰症和年龄相关的代谢疾病提供了治疗策略。
DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.